CN1547477A - Derivatives of partially desulphated glycosaminoglycans as heparanase inhibitors, endowed with antiangiogenic activity and devoid of anticoagulating effect - Google Patents
Derivatives of partially desulphated glycosaminoglycans as heparanase inhibitors, endowed with antiangiogenic activity and devoid of anticoagulating effect Download PDFInfo
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- CN1547477A CN1547477A CNA018236324A CN01823632A CN1547477A CN 1547477 A CN1547477 A CN 1547477A CN A018236324 A CNA018236324 A CN A018236324A CN 01823632 A CN01823632 A CN 01823632A CN 1547477 A CN1547477 A CN 1547477A
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- heparin
- desulfurization
- acid
- alduronic acid
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Abstract
Partially desulphated glycosaminoglycan derivatives are described, particularly heparin, and more particularly formula (I) compounds where the U, R and R1 groups have the meanings indicated in the description. Said glycosaminoglycan derivatives are endowed with antiangiogenic and heparanase-inhibiting acitivity ans are devoid of anticoagulant activity.
Description
The present invention relates to the acidifying glycosaminoglycans derivant of partial desulfurization, heparin particularly, its preparation method, it is used for the treatment of disease as active component in preparation, tumor for example, comprise the transfer form tumor, and can benefit from the application in the medicine of any treatment indication that suppresses heparanase (heparanase) and contain their pharmaceutical composition.
The prior art situation
The research (Is r.Med.Assoc.J.2000,2, the 37-45 that in the TumorBiological Research of Hadassah-Hebrew University Hospital-Israel Unit, carry out; J.Med.Chem.2000,43,2591-600; Invasion Metastasis 1994-95,14,290-302; Exp.Cell Res.1992,201,208-15; ) pay close attention to heparin binding growth factor, Heparan sulfate and Heparan sulfate digestive enzyme (heparanase) participates in tumor-blood-vessel growth and transfer.Having used these studies and screens and evaluation has effective heparanase and suppresses active heparin derivatives and heparin/Heparan sulfate analogies (Nature Med.1999,5,735-6; Science, 1999,285,33-4].
Tumor cell discharges heparanase, and this is a kind of interior type-β-D-glycuronidase, and its degraded is at the polysaccharide chain of the heparan sulfate proteoglycan on the cell surface and in extracellular matrix.
Heparanase having been participated in tumor-blood-vessel growth is associated with it discharges bFGF (FGF-2) and other somatomedin from it is stored in storage storehouse in the ECM (extracellular matrix) ability.These somatomedin provide the mechanism of inducing neovascularity to generate under normal and pathologic condition.
Therefore, heparanase may not only promote tumor cell invasion and transfer, but also promotes tumor-blood-vessel growth, and the two all is the committed step of tumour progression.
The specific inhibitor of heparanase stops the release of somatomedin and the breaking of activation and ECM of being stored by Heparan sulfate, and is regarded as developing the approach very likely of cancer therapy drug.
So for anti-angiogenic medicaments, a kind of possible treatment approach is an effectively and optionally heparanase inhibitors of exploitation.
Can be referring at the applicant WO 01/55221 under one's name about the discussion of angiogenesis.
The important participation of another of heparanase is inflammation and autoimmune.In fact, heparanase activity also leaves circulation and causes inflammatory relevant with the ability of autoimmunity reaction with immune active cell.Platelet, granulocyte, T and bone-marrow-derived lymphocyte, macrophage and mastocyte are relevant with heparanase activity degraded Heparan sulfate with the interaction of interior subcutaneous ECM.This enzyme is as discharging in (being lysosome, specific granule) from the intracellular region chamber the reaction of multiple different activation signals, and this shows its participation of being regulated and existence in inflammatory site and autoimmunity damage.(be the incidence rate that the treatment of the low molecular weight heparin-LMWH) laboratory animal of non-anticoagulant kind has significantly reduced experimental autoimmune encephalomyelitis in laboratory animal (EAE), adjuvant arthritis and transplant rejection, this shows and can use heparanase inhibitors to suppress autoimmunity and inflammatory diseases with heparanase inhibitors.
Heparin
Heparin is the heterogeneous mixture with naturally occurring polysaccharide of different length and different degree of sulfation, it has anticoagulating active, and is excretory by the connective tissue mast cell that is present in liver (at first separating from liver), muscle, lung, thymus and the spleen.
Except sequence of rules, in heparin, identified sequence corresponding to the avtive spot of antithrombin activity.
The antitumor of heparin and derivant thereof and antimetastatic activity are because due to the ability of its inhibition heparanase, blocking-up somatomedin and adjusting angiogenesis.
Heparan sulfate (HS)
Heparan sulfate (HS) is ubiquitous protein ligands.Albumen and HS chain combination have produced to the simple fixation of proteolysis resistant effect or protect specificity to regulate for example various effects of angiogenesis of biological activity.
Sugared skeleton in heparin and the Heparan sulfate (HS) is made of alternative D-glycosamine (GlcN) and hexuronic acid (GlcA or IdoA).
In heparin, the GlcN residue mainly is that N-is Sulfated, and in HS, they are that N-is Sulfated, are again that N-is acetylizad, have a small amount of unsubstituted NH
2Group.
The average O-sulphation of HS is lower than heparin.
For example tumor, the particularly application of neoplasm metastasis aspect have been subjected to the active serious restriction of anticoagulant heparin to heparin at the treatment angiogenic disease.
Heparin has been carried out chemical modification,, preserved its antitumor character simultaneously to reduce its anticoagulant ability.
Glucuronic acid unit in the antithrombase site opened can reduce the affinity of heparin to antithrombase: like this, in use, heparin can have the anticoagulation of reduction, but still keeps angiogenesis inhibitor character.
Heparanase
Heparanase is the enzyme that belongs to endoglycosidase (interior type-β-D-glycuronidase) family, the interior glycosidic bond of the chain of its hydrolysis Heparan sulfate (HS) and heparin.
These endoglycosidase participate in tumor cell proliferation, neoplasm metastasis and neovascularity and generate.These enzymes are biological targets of anti-angiogenesis activity.A large amount of structures/activity relationship research (referring to people such as for example Lapierre F., Glycobiology, vol.6, (3), 355-366,1996) is arranged in scientific literature.Though there are a lot of aspects still to remain to be clarified, but reported the inhibiting research of relevant heparin and derivant thereof to heparanase, use special test to cause occurring consideration to structure type, it can be used as to instruct and obtains derivant new, that selectivity is stronger.
In people's such as above-mentioned Lapierre article, it is to obtain by 2-O desulfurization acidify or " glycol cracking (glycol split) " (use periodate oxidation, use sodium borohydride reduction then) that heparin derivatives is described to.Partly kept the anti-angiogenesis activity of heparin in these these derivants that are defined as " 2-O-desulfurization acidify heparin " and " RO-heparin " respectively, described activity in the presence of corticosteroid by CAM experimental evaluation (ibid, the 360th page).
It is reported, be suppress heparanase than the N-acyl group heparin derivatives of the more proximate Heparan sulfate analogies of heparin activity only than N-sulphuric acid derivant weak slightly (Irimira T., Biochemistry 1986,25,5322-5328; Ishai-Michaeli R. waits the people, and Biochemistry 1992,31,2080-2088).
Heparin and FGF
FGF regulates various physiological processes for example cell growth and differentiation, but also participates in for example tumor-blood-vessel growth of pathological process.
FGF is somatomedin (families of 10 above polypeptide), and wherein acid (FGF-1) and basic FGF (FGF-2) are to study fullest, and it needs polysaccharide cofactor heparin or HS to combine with FGF receptor (FGFR) and activates it.
Though heparin and HS activation FGF cutter system really it be unclear that, known heparin/FGF/FGFR forms " three molecules " or " ternary " complex.
A kind of mechanism of supposition is that heparin and HS cause that so-called interlayer dimerization takes place FGF, thus the latter of dimerization and FGFR formation stabilized complex.
The antimetastatic activity of heparin derivatives
Perhaps, the ability that primary tumor produces metastatic cell is the subject matter that anticancer therapy is faced.
As if the heparin derivatives of remarkable ability with blocking-up heparanase can suppress the angiogenesis in primary tumor and the metastatic tumor equally.
In addition, suppress heparanase and reduced tumor cell is moved to other organ from primary tumor ability.
Have been found that, antimetastatic activity in animal model and heparin and heparin derivatives (people such as Bitan M., Isr.J.Med.Sci.1995,31,106-108) and other sulfated polysaccharides (Miao, people such as H.Q., Int.J.Cancer 1999,83,424-431 is with the list of references of wherein being quoted) heparanase to suppress ability relevant.For antimetastatic activity molecular weight dependence carried out studies show that, (Sciumbata, T. wait the people to the heparin of very low MW, InvasionMetastasis 1996,16,132-143) with many sulfate oligosaccharides (Parish, C.R., Deng the people, Cancer Res.1999,59,3433-3441) also keep significant antimetastatic activity.Though remove the metastasis potential that N-sulfate group (N-desulfurization acidify) can reduce heparin usually, with formed free NH
2(N-acetylation, N-hexanoylization (Bitan M., 1995) and N-succinylation (Sciumbata, T., 1996) afterwards, this active part recovers group N-acidylate.Antimetastatic activity and its O-degree of sulfation negative correlation (Bitan M., 1995) of heparin have been found.Yet the selectivity 2-O-desulfurization acidify of iduronic acid residue does not cause the remarkable decline of heparin antimetastatic activity, and (Glycobiology 1996,6,355-366) for Lapierre, F..
Generally speaking, inhibition of the heparanase of heparin and other sulfated polysaccharides and antimetastatic activity reduce (Bitan M., 1995 along with the decline of molecular weight and degree of sulfation; Parish, C.R., 1999).Yet these activity also depend on the sugar backbone (type of residue and the position of glycosidic bond) (Parish, C.R., 1999) of polysaccharide.Because it is unknown that the three dimensional structure in heparanase activity site remains, so be difficult to the predict what polysaccharide main chain and the sulphation pattern can suppress this enzyme most effectively.
Based on present knowledge, the structural requirement that helps the heparin-like molecule of angiogenesis suppression action can be divided into 2 classes according to the target of desire blocking-up:
A) suppress heparanase: though this enzyme identification and cracking contain N-acyl group-glycosamine-glucuronic acid (or N-sulphation glycosamine residue; referring to people J.Biol.Chem. such as for example D.Sandback-Pikas; 273; 18777-18780 (1998) and the list of references of wherein quoting) the heparin and the HS sequence of at least 8 monosaccharide units; but its inhibition can be finished (Bitan M. by the heparin fragment of being longer than ten tetroses effectively; 1995); or by extensive Sulfated shorter oligosaccharide for example sulphuric acid Fructus Hordei Germinatus hexose (MHS) and sulphuric acid phosphoric acid manna pentose (PI-88) are finished (Parish; C.R., 1999).Yet long heparin fragment and the Sulfated oligosaccharide of severe all are anticoagulant, and for possible anti-metastasis drug, this is the character that should be avoided;
B) suppress angiogenesis growth factor (fibroblast cell type: FGF-1 and FGF-2; Blood vessel endothelium type: VEGF; Blood vessel open type: VPF): for this, heparin sample chemical compound preferably has such sequence, length is at least 5 monosaccharide units, contain 2-sulphation iduronic acid and N, 6-sulphation glycosamine is (referring to people such as for example M.Maccarana, J.Biol.Chem., 268,23989-23905 (1993)).
Document discloses the little peptide (5-13 aminoacid) (US 5,399,667 of University of Washington) with anti-angiogenesis activity, and it is by working in conjunction with the thrombospondin receptor, or longer peptide (about 50 aminoacid).
(EP 0589719, Lilly) can be with IC for the platelet factor of known modification
50=7nM suppresses endothelium propagation.
Oligosaccharide fragment with anti-angiogenesis activity was also fully described: have been found that in fact, by changing glycosylation sequence, can improve the interaction selectivity.
In addition, heparin also can be used as the material carrier of some steroid for example that self has blood vessel formation against function, and this is to adopt the affinity of heparin to vascular endothelial cell; Referring to the WO93/18793 of for example University of Texas and Imperial Cancer Research Technology, heparin wherein required for protection by the unstable junctional complex of acid for example the adipic acid hydrazine be attached on the hydrocortisone.This blood vessel formation against function of puting together molecule is greater than not puting together molecule when administration (even at the same time).
In Biochim.Biophys.Acta (1996), 1310, among the 86-96, to have described at C-20 via hydrazone groups and the bonded heparin of steroid (for example hydrocortisone), its anti-angiogenesis activity is greater than these two kinds of unconjugated molecules.
The EP 0246654 of Daiichi Sc. has described and has carried out the sulfated polysaccharides with anti-angiogenesis activity that the II phase studies.Pharmacia ﹠amp; The EP 0 394 971 of Upiohn-Harvard Coll. has described has low Sulfated hexose-heparin fragment, and it can suppress the angiogenesis of endothelial cell growth and FGF-1 stimulation.The EP 0 618 234 of Alfa Wasserman has described the method that preparation has the semi-synthetic glycosaminoglycans of the heparin that carries nucleophilic group or heparinoid structure.The WO 95/05182 of Glycomed has described the multiple sulfated oligosaccharides with anticoagulant, angiogenesis inhibitor and anti-inflammatory activity.The US 5 of Glycomed, 808,021 have described the preparation 2-O, the method for 3-O desulfurization acidify heparin of non-depolymerization basically, and described heparin is at iduronic acid 2-position (I, 2-O) (A, desulfurization acidify percentage ratio 3-O) are about 99-about 97% of initial percentage with glucosamine units 3-position.In the method, the desulfurization acidify is at divalent metal, and for example calcium ion or copper ion carry out under existing, then with the products therefrom lyophilization.Gained desulfurization acidify heparin has anti-angiogenesis activity.Yeda Res﹠amp; The EP 0 251 134 of Dev Co Ltd etc. discloses the application of heparin or derivatives thereof in prevention homograft rejection and treatment autoimmune disease of inferior blood coagulation dosage.Wherein the activity of heparin realizes by suppressing heparanase.The WO 88/05301 of Univ.Australian Nat. discloses metastasis and/or the anti-inflammatory composition that comprises as the sulfated polysaccharides of heparanase inhibitors.Heparin, fucoidin, sulphuric acid pentosan, dextran sulfate wherein are provided.The WO 92/01003 of Univ.Texas System discloses the application as heparanase inhibitors of the heparin derivatives that do not have anticoagulating active.These derivants have sulfoamino-group or O-sulfate group, and M.W. is 1000-15000, and each end monomer unit is to have the monomeric repeating unit that is attached to the terminal O atom on the blocking group.WO 94/14851 and the WO 96/06867 of Glycomed provide 2-O, 3-O-desulfurization acidify mucosal heparin or its fragment, and it is at least 96.7% desulfurization acidify in the 2-O position, and at least 75% desulfurization acidify in the 3-O position can be used as non-anticoagulant heparanase inhibitors.The WO95/09637 of Glycomed and WO 96/09828 disclose the height sulphation Fructus Hordei Germinatus oligose chemical compound with heparin sample characteristic.The WO 95/30424 of Glycomed provides to have heparanase and suppresses active 6-O-desulfurization acidify heparin or its fragment.The WO 96/33726 of Univ.Australian Nat. discloses as having the sulfated oligosaccharides that heparanase suppresses active heparinoid analogies.The WO 01/35967 of Knoll AG provides by using heparanase inhibitors and has treated the method for cardiac insufficiency and associated conditions; in described heparanase inhibitors, mentioned COOH group with partial reduction; or to small part N-desulfurization acidify and N-acetylation; or to small part N, O-desulfurization acidify and N-be sulphation or the acetylizad heparin of O-again.
The objective of the invention is to find best glycosaminoglycans structure, to suppress based on heparanase and/or FGF somatomedin inhibition mechanism generation anti-angiogenesis activity.Another object of the present invention provides the medicine with anti-angiogenesis activity, and the typical side effects that described medicine does not have heparin derivatives basically is anticoagulating active for example.
Disclose glycosaminoglycans at the applicant WO 01/55221 under one's name, particularly the desulfurization acescency is no more than the desulfurization acidify heparin of total alduronic acid unitary 60%.These derivants that provided have anti-angiogenesis activity, and do not have anticoagulating active.Described chemical compound is brought into play its anti-angiogenesis activity and is based on and has suppressed FGF.Do not predict the activity that suppresses heparanase.
WO 01/55221 also provides the modification that comprises glycosamine residue heparin with very general description, and it has different N-desulfurization acescency and optional acetylation wholly or in part subsequently.N-desulfurization acidify and optional acetylizad wholly or in part subsequently step are not clearly described in the generality instruction of described list of references.
Summary of the invention
Have now found that; has different N for comprising-desulfurization acescency and the optional glycosaminoglycans of the glycosamine residue of N-acidylate (preferred N-acetylation) wholly or in part subsequently; for example heparin sample glycosaminoglycans, heparin or modification heparin; it is carried out in check iduronic acid unit 2-O-desulfurization acidification; the highest to be no more than total alduronic acid unitary 60% until the desulfurization acescency, can keep the angiogenesis character of somatomedin mediation.
Surprisingly, disclosed 2-O-desulfurization acidify heparin also is a heparanase inhibitors among the above-mentioned WO 01/55221.Discovery can further strengthen this character by not Sulfated uronic acid residue is carried out the glycol cracking.Also find; glycol cracking-cause anticoagulating active is chemical modification (the Casu B. of forfeiture significantly; Deng the people; Arzneim.Forsch. (Drug Res.) 1986; 36; 637-642) significantly strengthened the heparanase inhibition activity of part N-acetylation heparin and 2-O-desulfurization acidify chemical compound, wherein said part N-acetylation heparin is by 50%N-desulfurization acidify, then the gained free amine group is carried out the N-acetylation and obtains.
The desulfurization acidify of carrying out under condition of the present invention also makes and has formed the iduronic acid unit that has the oxyranic ring at prosposition.Under condition of the present invention, open the oxyranic ring and cause forming L-iduronic acid or L-galacturonic acid acid unit.
An object of the present invention is described glycosaminoglycans derivant has heparanase and/or FGF somatomedin in preparation and suppresses application in the active medicine.
According to the present invention, described glycosaminoglycans derivant is heparin sample glycosaminoglycans preferably.According to the present invention, described glycosaminoglycans derivant is the heparin of modification, wherein comprises to have different N-desulfurization acescency and optional acetylizad wholly or in part subsequently glycosamine residue.
In a special embodiment, the present invention relates to formula (I) chemical compound
Wherein the U ring can have following meanings:
X and X ' can be identical or different, be aldehyde radical or-CH
2-D group, wherein D is the residue of hydroxyl or aminoacid, peptide or sugar or oligosaccharide;
R and R
1Can be identical or different, be SO
3, C
1-8Acyl residue, described residue can be chosen wantonly and carry at least one other carboxyl; Acetyl group, caproyl, succinyl group, valeryl are preferred acyl residues;
N and m can be identical or different, can be 1-40; N+m's and be 6-40; M: the n ratio is 10: 2-1: 1;
Symbol
Be meant that the unit of representing with m and n is along the polysaccharide chain statistical distribution, and need not to distribute in order.
Can choose the C that carries at least one other carboxyl wantonly
1-8The example of acyl residue is acetyl group, propiono, bytyry, valeryl, caproyl, heptanoyl group and all possible isomer, oxalyl group, malonyl, succinyl group, valeryl, glutaryl; Acetyl group, caproyl, valeryl are preferred acyl residues.
As R or R
1When being the N-acyl group, they are preferably R+R
1The 40-60% of sum.M is preferably greater than or equals n.N is preferably the 40-60% of m+n sum.
Wherein R and R
1Be C
1Or C
3-C
8Above-mentioned formula (I) chemical compound of acyl residue is new.
Chemical compound as theme of the present invention is characterised in that, suppress heparanase with efficient, therefore have noticeable angiogenesis inhibitor characteristic, can be used as active component and be used to prepare and be used for treating the disease that to benefit from the disease that suppresses heparanase, generate based on abnormal vascular and the medicine that particularly is used for treating metastatic tumor.
The compounds of this invention also suppresses FGF.
Advantageously, The compounds of this invention shows the anticoagulant character of reduction (if not non-existent words), therefore avoids or reduced the typical side effects of heparin.Another advantage is from the following fact, promptly The compounds of this invention can with instrument analysis technology for example NMR spectrum characterize, allow to see the process control of absolute ideal thus from industrial point of view.
For the modification heparin, when the preparation angiogenesis inhibitor, molecular weight (MW) has very important function equally.As everyone knows, in fact, be up to molecular weight (MW) reduction that is equivalent to the unitary value of pentasaccharides and do not cause the anti-angiogenesis activity forfeiture.On the other hand, establishedly be that although the heparin chain is the activation of facilitating rather than suppresses FGF when surpassing certain-length, they are comparison short chain even better heparanase inhibitors.Yet for suppressing heparanase, best chain length depends on the structure (sugar backbone, key position, sulphation pattern) of inhibitor, and should establish the best chain length of any novel potential inhibitor.
Detailed Description Of The Invention
This paper specifically openly comprises and has different N-desulfurization acescency and the optional The compounds of this invention of acetylizad wholly or in part glycosamine residue subsequently, and they are claimed as noval chemical compound.
The desulfurization acescency is meant that not Sulfated iduronic acid accounts for the percentage ratio of the total alduronic acid that exists originally in the initial heparin.An initial preferable range of desulfurization acidify percentage ratio is about 40-about 60%.
In the middle of formula (I) chemical compound, first preferred chemical compound is the acidifying heparin of part 2-O-desulfurization, and its molecular weight (MW) is 11200, and polydispersity index D is 1.3, and the desulfurization acescency is 1.99 (with SO
3 -: COO
-Mol ratio is represented), the percentage ratio that the alduronic acid of modification accounts for total alduronic acid is about 50%.Described chemical compound (hereinafter also being called ST1514) is included in the formula (I), wherein except other corresponding definition, and m: n=1: 1, and be to distribute along polysaccharide chain with rule, alternative mode with the unit that m and n represent.
Second preferred chemical compound is the acidifying LMW heparin of part 2-O-desulfurization, and its molecular weight (MW) is 3050, and polydispersity index is 2.2, and the desulfurization acescency is 1.99 (with SO
3 -: COO
-Mol ratio is represented), the percentage ratio that the alduronic acid of modification accounts for total alduronic acid is about 50%.Described chemical compound (hereinafter also being called ST2010) is included in the formula (I), wherein except other corresponding definition, and m: n=1: 1, and be to distribute along polysaccharide chain with rule, alternative mode with the unit that m and n represent.This chemical compound is to obtain like this: with the ST1514 depolymerization, then with the aldehyde radical reduction, most of like this its reducing end residue is the dehydration mannose residue with nitrous acid:
The 3rd preferred chemical compound is the acidifying LMW heparin of part 2-O-desulfurization, and its molecular weight is Mn=5800, and Mw=7520, polydispersity index are 1.294, and the percentage ratio that the alduronic acid of modification accounts for total alduronic acid is about 50%.Described chemical compound (hereinafter also being called ST2184) is included in the formula (I), wherein except other corresponding definition, and m: n=1: 1, and be to distribute along polysaccharide chain with rule, alternative mode with the unit that m and n represent.This chemical compound is to obtain like this: with the ST1514 depolymerization, then with the aldehyde radical reduction, most of like this its reducing end residue is the dehydration mannose residue with nitrous acid.
The 4th preferred chemical compound is part N-desulfurization acidify and N-reacetylation heparin, and its molecular weight (MW) is 11200, and polydispersity index is 1.3, and the desulfurization acescency is 1.6 (with SO
3 -: COO
-Mol ratio is represented), the percentage ratio that the alduronic acid of modification accounts for total alduronic acid is about 30%.Described chemical compound (hereinafter also being called ST1518) is included in the formula (I), wherein except other corresponding definition, and R+R
150% of sum is the N-acetyl group.
The 5th preferred chemical compound is part N-desulfurization acidify and N-reacetylation LMW heparin, and its molecular weight is Mn=4780, and Mw=10000, polydispersity index are 2.092, and the percentage ratio that the alduronic acid of modification accounts for total alduronic acid is about 30%.Described chemical compound (hereinafter also being called ST2168) is included in the formula (I), wherein except other corresponding definition, and R+R
150% of sum is the N-acetyl group.
The 6th preferred chemical compound is part N-desulfurization acidify and N-reacetylation heparin, and its molecular weight is Mn=10890, and Mw=22370, polydispersity index are 2.054.Described chemical compound (hereinafter also being called ST2037) is included in the formula (I), wherein except other corresponding definition, and R+R
127% of sum is the N-acetyl group.
The 7th preferred chemical compound is part N-desulfurization acidify and N-reacetylation heparin, and its molecular weight is Mn=10210, and Mw=21270, polydispersity index are 2.083.Described chemical compound (hereinafter also being called ST2038) is included in the formula (I), wherein except other corresponding definition, and R+R
139% of sum is the N-acetyl group.
The 8th preferred chemical compound is part N-desulfurization acidify and N-reacetylation heparin, and its molecular weight is Mn=11070, and Mw=22000, polydispersity index are 1.987.Described chemical compound (hereinafter also being called ST2041) is included in the formula (I), wherein except other corresponding definition, and R+R
164% of sum is the N-acetyl group.
The 9th preferred chemical compound is part N-desulfurization acidify and N-reacetylation heparin, and wherein to account for the percentage ratio of total alduronic acid be about 30% to the alduronic acid of Xiu Shiing.Described chemical compound is included in the formula (I), wherein except other corresponding definition, and R+R
127% of sum is N-acetyl group (ST2185).
The tenth preferred chemical compound is part N-desulfurization acidify and N-reacetylation heparin, and wherein to account for the percentage ratio of total alduronic acid be about 30% to the alduronic acid of Xiu Shiing.Described chemical compound (hereinafter also being called ST2186) is included in the formula (I), wherein except other corresponding definition, and R+R
139% of sum is the N-acetyl group.
The 11 preferred chemical compound is part N-desulfurization acidify and N-reacetylation heparin, and wherein to account for the percentage ratio of total alduronic acid be about 30% to the alduronic acid of Xiu Shiing.Described chemical compound (hereinafter also being called ST2187) is included in the formula (I), wherein except other corresponding definition, and R+R
164% of sum is the N-acetyl group.
The 12 preferred chemical compound is part 2-O-desulfurization acidify heparin, and its molecular weight (MW) is 12900D, and polydispersity index D is 1.5, and the desulfurization acescency is 1.9 (with SO
3 -: COO
-Mol ratio is represented), the percentage ratio that the alduronic acid of modification accounts for total alduronic acid is: 5% epoxy radicals, 29% oxidation and reductive uronic acid residue.Described chemical compound (hereinafter also being called ST1513) is included in the formula (I), wherein except other corresponding definition, and m: n=1: 1, and be to distribute along polysaccharide chain with rule, alternative mode with the unit that m and n represent.
The 13 preferred chemical compound is part 2-O-desulfurization acidify heparin, and its molecular weight (MW) is 9200D, and polydispersity index D is 1.5, and the percentage ratio that the alduronic acid of modification accounts for total alduronic acid is: 11% epoxy radicals, 27.5% oxidation and reductive uronic acid residue.Described chemical compound (hereinafter also being called ST1515) is included in the formula (I), wherein except other corresponding definition, and m: n=1: 1, and be to distribute along polysaccharide chain with rule, alternative mode with the unit that m and n represent.
The 14 preferred chemical compound is part 2-O-desulfurization acidify heparin, and its molecular weight (MW) is 11000D, and polydispersity index D is 1.5, and the desulfurization acescency is 1.93 (with SO
3 -: COO
-Mol ratio is represented), the percentage ratio that the alduronic acid of modification accounts for total alduronic acid is: 5% epoxy radicals, 29% oxidation and reductive uronic acid residue.
The preparation of compound S T1514, ST1513, ST1516 and ST1515 specifically is disclosed among the WO 01/55221.
Part 2-O-desulfurization acidify derivant of the present invention is according to disclosed method preparation among the above-mentioned WO01/55221.
As for N-desulfurization acidify of the present invention and optional N-acetylation glycosaminoglycans, they can make by the method that can also prepare 2-O-partial desulfurization acidify heparin, and described method comprises:
A) carry out N-desulfurization acidify by following operation: with the sulfoamino-group residue at DMSO: H
2O95: 5 v: solvolysis hydrolysis 0.5-8 hour under room temperature among the v, even more preferably from about 2 hours, to remove sulfate groups wholly or in part in glycosamine residue 2-position;
B) by following operation with described in glycosamine residue 2-position the acidifying group N-of desulfurization acidylate wholly or in part: in alkaline aqueous solution (pH8-9) with acylating agent for example acyl anhydrides handle, to be created on the glycosamine residue 2-position group of acidylate wholly or in part; Then the gained chemical compound is carried out following step c), d) or e) and f-g), or directly carry out following step f);
C), preferred 50-70 ℃, even more preferably from about carry out alkali treatment under 65 ℃ of temperature, cause being removed and forming epoxide group in the sulfate groups of the controlled percentage ratio of iduronic acid 2-position room temperature-Yue 100 ℃; If necessary
D), in about 50 ℃-Yue 100 ℃, open described epoxide ring under preferred about 70 ℃ of temperature, to produce the galacturonic acid residue at about pH 7; Perhaps
E), open described epoxide ring under preferred about 25 ℃ of temperature, to produce the iduronic acid residue at about 0 ℃-30 ℃; If necessary
F) with sodium metaperiodate with glycol oxidation, to open the glucosides ring and to form the residue of 2 aldehyde radical/modifications; If necessary
G) described aldehyde radical is reduced into primary alconol and if necessary, the represented non-hydroxyl group of different implications that the D groups converted is become as provides in formula (I);
H) optional the chemical compound that obtains is carried out acid hydrolysis in step g), to obtain and the corresponding oligosaccharide of sequence of rules, preferably by realizing with the nitrous acid deaminizating.Cause obtaining having the residue formed by alduronic acid and having the LMW chemical compound of dehydration mannose residue by this reaction that the key between cracking N-glucosamine sulfate residue and the next alduronic acid obtains the LMW heparin through being usually used at reducing end at non-reducing end, can be by the dehydration mannose residue further being modified into dehydration mannitol with sodium borohydride reduction.The LMW chemical compound that is obtained contains the cracked iduronic acid residue of at least one glycol; Perhaps
I) product that will obtain in step g) with the enzyme that is selected from lyases, heparinase, heparanase or coordinate carries out the part enzymatic hydrolysis, to obtain oligosaccharide, preferred tetrose or eight sugar, its non-reduced terminal residue is made up of unsaturated iduronic acid, the reduction residue is made up of the N-glucosamine sulfate, and contains at least one open loop iduronic acid residue.
I) randomly handle chemical compound that in step c), obtains or the product that in step d), obtains by the part enzymatic hydrolysis; If necessary
J) will be at step b), c) and one of f) in the product part 6-O-desulfurization acidify that obtains; Perhaps
K) partially or completely the acidifying initial heparin of 6-desulfurization carries out step b), c) and f).
2-O-desulfurization acidify derivant of the present invention is with saving step a) and b) said method obtain.
The inventive method can also illustrate by following reaction scheme:
According to the present invention, preferred chemical compound is:
The acidifying heparin of-part 2-O-desulfurization, it can be by saving step a) and b) said method obtain, wherein step c) is to carry out 45 minutes at 60 ℃, step d) is carried out in pH7 at 70 ℃, its molecular weight (MW) is 11200, and polydispersity index D is 1.3, and the desulfurization acescency is 1.99 (with SO
3 -: COO
-Mol ratio is represented), the percentage ratio that the alduronic acid of modification accounts for total alduronic acid is about 50% (hereinafter also being called ST1514);
The acidifying LMW heparin of-part 2-O-desulfurization, it can be by saving step a) and b) said method obtain, wherein step c) is to carry out 45 minutes at 60 ℃, step d) is carried out in pH7 at 70 ℃, carry out step f), g then) and carry out h by deaminizating), its molecular weight (MW) is 3050, and polydispersity index D is 2.2, and the desulfurization acescency is 1.99 (with SO
3 -: COO
-Mol ratio is represented), the percentage ratio that the alduronic acid of modification accounts for total alduronic acid is about 50% (hereinafter also being called ST2010);
The acidifying LMW heparin of-part 2-O-desulfurization, it can be by saving step a) and b) said method obtain, wherein step c) is to carry out 45 minutes at 60 ℃, step d) is carried out in pH7 at 70 ℃, carry out step f), g then) and carry out h by deaminizating), its molecular weight is Mn=5800, Mw=7520, polydispersity index D is 1.294, and the percentage ratio that the alduronic acid of modification accounts for total alduronic acid is about 50% (hereinafter also being called ST2184);
-heparin N-acetyl group (50%); it can obtain by said method; wherein step a) was carried out 2 hours in room temperature; step b) was carried out step c), d 2 hours at 4 ℃), e) save, step f) is carried out a night at 4 ℃; step g) was carried out 3 hours in room temperature; its molecular weight (MW) is 11200, and polydispersity index D is 1.3, and the desulfurization acescency is 1.6 (with SO
3 -: COO
-Mol ratio is represented), the percentage ratio that the alduronic acid of modification accounts for total alduronic acid is about 30% (hereinafter also being called ST1518).
-LMW heparin N-acetyl group (50%); it can obtain by said method; wherein step a) was carried out 2 hours in room temperature; step b) was carried out 2 hours at 4 ℃; step c), d), e) save; step f) is carried out a night at 4 ℃; step g) was carried out 3 hours in room temperature; step h) by carrying out 17 minutes based on 4 ℃ with the nitrous acid deamination; use borohydride reduction aldehyde radical 3 hours in room temperature then, its molecular weight is Mw=4780, Mn=10000; polydispersity index D is 2.092, and the percentage ratio that the alduronic acid of modification accounts for total alduronic acid is about 30% (hereinafter also being called ST2168).
-heparin N-acetyl group (27%); it can obtain by said method; wherein step a) was carried out 2 hours in room temperature; step b) was carried out 2 hours at 4 ℃; step c), d), e), f), g), h) save; its molecular weight is Mn=10890, and Mw=22370, polydispersity index D were 2.054 (hereinafter also being called ST2037).
-heparin N-acetyl group (39%); it can obtain by said method; wherein step a) was carried out 2 hours in room temperature; step b) was carried out 2 hours at 4 ℃; step c), d), e), f), g), h) save; its molecular weight is Mn=10210, and Mw=21270, polydispersity index D were 2.083 (hereinafter also being called ST2038).
-heparin N-acetyl group (64%); it can obtain by said method; wherein step a) was carried out 2 hours in room temperature; step b) was carried out 2 hours at 4 ℃; step c), d), e), f), g), h) save; its molecular weight is Mn=11070, and Mw=22000, polydispersity index D were 1.987 (hereinafter also being called ST2041).
-heparin N-acetyl group (27%); it can obtain by said method; wherein step a) was carried out 2 hours in room temperature; step b) was carried out 2 hours at 4 ℃; step c), d), e), f), g), h) save, the percentage ratio that the alduronic acid of modification accounts for total alduronic acid is about 30% (also being called ST2185 hereinafter).
-heparin N-acetyl group (39%); it can obtain by said method; wherein step a) was carried out 2 hours in room temperature; step b) was carried out 2 hours at 4 ℃; step c), d), e), f), g), h) save, the percentage ratio that the alduronic acid of modification accounts for total alduronic acid is about 30% (also being called ST2186 hereinafter).
-heparin N-acetyl group (64%); it can obtain by said method; wherein step a) was carried out 2 hours in room temperature; step b) was carried out 2 hours at 4 ℃; step c), d), e), f), g), h) save, the percentage ratio that the alduronic acid of modification accounts for total alduronic acid is about 30% (also being called ST2187 hereinafter).
The preparation of compound S T1514, ST1513, ST1516 and ST1515 specifically is disclosed among the WO 01/55221.
Molecular weight can pass through HPLC-GPC (high performance liquid chromatography-gel permeation chromatography) and measure.The desulfurization acescency is measured by conductimetry, and the percentage ratio of the alduronic acid of modifying be by
13C-NMR measures.
MW is a molecular weight, and D is the polydispersity index of representing with MW/Mn.
According to the present invention, raw material is the glycosaminoglycans of separate sources, preferred natural heparin.Also may use N, the degree of 6 di-sulfates is the heparin of the chemical modification of 0-100%.Use has the product of different 6-O-sulphation glycosamine content as raw material, the length of iduronic acid of opening of scalable and the sequence of rules between another.The glycosaminoglycans of the present invention that the glucosides ring is opened is called the RO derivant by those skilled in the art as usual, and this is meant this glucosides ring by Oxidation, reduces then and the (redox-RO) that is opened.Opening usually of this glucosides ring also is called " glycol cracking ", and why like this appellation is because formed two primary hydroxyls that are present in the open loop.Such chemical compound also is called " RO " or " glycol cracking " derivant.
In another embodiment of the present invention, aldehyde that forms by above-mentioned ring-opening reaction (" glycol cracking ") and primary hydroxyl also can make subsequently functionalized taken place self.Therefore, formula (I) chemical compound can also carry on the cracked primary hydroxyl derived from glycol as mentioned about X and the defined identical or different group of X ', for example from monosaccharide or preferred 2 or 3 unitary oligosaccharide of aminoacid to one an above element length or peptide group.
Wherein X and X ' are-CH
2The formula of OH (I) chemical compound also can be used as the carrier of other types of drug, by with suitable combination of heparin part, described heparin part can provide stable key under normal compounding pharmaceutical production and storage requirement, and in vivo, preferably discharges the medicine that is transported near target organ.The example of the medicine that can transport is steroid class and non-steroidal antiinflammatory drugs, corticosteroid and other medicines with metastasis effect, in this case, as The compounds of this invention and its summation of independent intrinsic activity of bonded metastasis agent, the metastasis effect will advantageously be strengthened, and has higher target selectivity and the lower such associated advantages of system toxicity.The example of these medicines is inhibitors of metalloproteinase.Other medicine that can usefully transport is the medicine that works on endothelin level.Wherein X and X ' are not the yet carriers of useful as drug of formula (I) chemical compound of hydroxyl or aldehyde, in this case, X and X ' group will work the molecule that is transported, be " sept " between glycosaminoglycans of the present invention and the molecule that plays carrier function, these situations may be owing to the reason of pharmacokinetics or pharmacodynamics but expectation.
For the The compounds of this invention derived from heparin, they are with those skilled in the art well-known technology, by N-desulfurization acidify, and N-acidylate and making then by the heparin raw material.For example, N-desulfurization acidify is performed such: at DMSO: H
295: 5 v of O solution: among the v in room temperature solvolysis 0.5-8 hour, then under alkali condition, with for example acyl anhydrides (being acetyl group, caproyl, succinyl group, valeryl) N-acidylate.
Ensuing 2-O-desulfurization acidify be alkaline reagent for example in the presence of the sodium hydroxide in room temperature-100 ℃, preferred 50-70 ℃, for example under 60 ℃ of temperature, carry out the sufficiently long time to obtain required 2-O-desulfurization acidify.2-O-desulfurization acidify is that for example reactant concentration, temperature and response time are controlled by acting on procedure parameter.Preferred examples is to keep constant concentration: substrate (glycosaminoglycans) concentration is 80mg/ml, and NaOH concentration is 1M, 60 ℃ steady temperature, and the acidifying response time of desulfurization was controlled at 15-60 minute.Those skilled in the art can come the change condition according to the general knowledge of code test and experimental implementation error and individuality, for example improve reaction temperature and shorten the response time.
But handle generating feature on desulfurization acidify unit, there being the intermediate product of epoxide ring with alkaline reagent.Making us very surprised is that verified, these intermediate have the heparanase inhibition activity of the formula of being similar to (I) chemical compound.Therefore therefore, another object of the present invention is a part 2-O-desulfurization acidify heparin, is the heparin with electric charge of minimizing, and particularly 2-O-desulfurization acidify is no more than the derivant of 60% heparin, it is characterized in that having epoxide ring in desulfurization acidify site.Feature is to exist the described chemical compound of epoxide ring also to belong in the scope of the invention.
After forming epoxide ring, described epoxide ring to be opened, this adopts known technology equally.The percentage ratio of formed epoxide is by at about 55ppm
13Ratio calculating between C-NMR signal area (be contain the carbon 2 of alduronic acid ring of epoxide and 3 feature) and all number anomeric carbon signal areas (C1 of glycosamine and uronic acid residue).If under heating condition, carry out open loop, then obtain the galacturonic acid residue, and if the open loop of epoxide ring is to carry out under cool condition, then obtain the iduronic acid residue.The preferred embodiment that contains the chemical compound of epoxide ring can obtain by said method, and the epoxidation glucuronic acid content is respectively 14% (hereinafter being called ST1509), 24% (hereinafter being called ST1525) and 30% (hereinafter being called ST1526) those.
According to said method partial desulfurization acidify heparin is carried out " glycol cracking " (being abbreviated as RO) and Smith degraded (being abbreviated as SD) then.
Perhaps, formula (I) chemical compound can not obtain via epoxide intermediates yet, that is to say, obtains by direct glycol cracking and the degraded of Smith subsequently.
Said method also causes forming wherein, and X and X ' group are-CH
2The formula of OH (I) chemical compound.
For not being-CH
2The X of OH and X ', those skilled in the art can adopt and be used for hydroxyl is changed into other method of group (referring to for example reaction scheme of 14-15 page or leaf, compound S T1828, ST1829, ST1917 and ST1919) as defined above.For example, can carry out (people such as Hoffmann J. by handle the intermediate aldehydes derive from the glycol lytic response with reductive amination process with puting together of aminoacid or peptide, Carbohydrate Research, 117,328-331 (1983)), this reaction can be carried out in aqueous solvent, and can not hinder the maintenance of heparin structure.
If necessary, and what also constitute another object of the present invention is that usable acid reagent is for example further degraded formula (I) chemical compound at pH4 under suitable pH condition, generate to keep the oligosaccharide mixture of angiogenesis inhibitor character.
Equally, the objective of the invention is step g), h by said method), i) and j) in the middle of the chemical compound that obtains of a step.
The objective of the invention is pharmaceutical composition, wherein contain at least a formula (I) chemical compound as active component, described formula (I) chemical compound is united separately or with one or more formulas (I) chemical compound, for example epoxidation intermediate associating of perhaps described formula (I) chemical compound and above-mentioned N-acyl group-desulfurization acidify heparin; The latter also can be used alone as and be the active component in the pharmaceutical composition.Active component of the present invention can with commonly used suitable carriers and/or excipient in the pharmaceutical technology, for example at " Remington ' s Pharmaceutical Sciences Handbook ", those that describe in the latest edition form mixture.The present composition will contain the active component for the treatment of effective dose.Dosage by those skilled in the art for example clinicist or attending doctor according to the disease type and the decision of patient body situation of desire treatment, perhaps with the administration of other active component together.For example, dosage range can be 0.1-100mg/kg.
The example of pharmaceutical composition be Orally-administrable or parenteral route, intravenous, intramuscular, subcutaneous, transdermal administration or be nose with or the oral cavity with those of spray form.The pharmaceutical composition that is applicable to these purposes is tablet, hard or soft capsule, powder, solution, suspension, syrup and the solid dosage forms that is used for temporarily preparing liquid preparation.The compositions that is used for parenteral administration is for example all intramusculars, intravenous and subcutaneous injection dosage form and solution, suspension and emulsion.What can also mention is Liposomal formulation.Tablet also comprises the form that is used for the sustained release active component, they can be the oral administration forms, with the tablet of suitable layer coating, microcyst powder, with the complex of cyclodextrin, also can be reservoir type, for example the reservoir type of subcutaneous administration is for example store storehouse injection or implant.
The compounds of this invention has anti-heparanase and anti-angiogenesis activity.This makes that they are suitable for preparing and is used for the treatment of the individuality that the angiogenesis of suffering from change maybe needs to suppress the treatment of heparanase activity, generally is the medicine of mammal, particularly individual human.
The example of the disease of available Drug therapy of the present invention is a primary tumor, metastatic tumor, diabetic retinopathy, psoriasis, retrolental fibroplasia, the restenosis of postangioplasty, coronary artery bypass, inflammation, arthritis, autoimmune disease, homograft rejection, cardiovascular disease, the fiber proliferative disease, the disease that unusual platelet aggregation causes, the disease that smooth muscle proliferation causes, the Goodpasture syndrome, acute glomerulonephritis, the neonate pulmonary hypertension, asthma, congestive heart failure, adult's pulmonary hypertension, renal vascular hypertension, proliferating retinopathy, experimental autoimmune encephalomyelitis, multiple sclerosis, insulin dependent diabetes mellitus (IDDM), inflammatory bowel, ulcerative colitis, segmental enteritis.
Advantageously, The compounds of this invention does not have the typical side effects of heparin basically.Particularly, The compounds of this invention does not have anticoagulating active basically.To those skilled in the art, do not have such activity basically, on the angle of clinical practice, being meant does not have or only has insignificant activity.
The heparinoid enzyme inhibition activity is people such as (, 1995) the Bitan M. that measures according to the method that Vlodavsky ' s group sets up.This method is based on the degree of the heparan sulfate chains fracture of the heparan sulfate proteoglycan (HSPG) that evaluation causes by heparanase.The extracellular matrix of sulfate labelling (ECM) is the most frequently used HSPG source.Lacking and existing under the situation of test compounds of progressive concentration, the ECM and the recombinant heparanase of sulfate labelling are cultivated at pH6.2.In order to estimate the generation of Dan Baijutang degraded, collect culture medium, be applied to the Sepharose6B post and (carry out gel filtration on 0.9 * 30cm).With PBS flow velocity eluting level part (0.2ml) with 5ml/ hour, and the counting radioactivity.With blue dextran labelling excluded volume (V
o), always comprise volume (V with phenol red labelling
t).With 0.5＜K
Av＜0.8 (peak II) elutes the degradation fragment of HS side chain from Sepharose 6B.Under the experiment condition of being reported, good heparanase inhibitors suppresses the HS fracture with 10 μ g/ml or littler concentration.
The result is as shown in table 1 below.
Table 1
Heparanase under 25 μ/ml-5 μ/ml dosage suppresses
| Suppress | ||
| Dosage | ??25μg/ml????10μg/ml????5μg/ml | |
| Heparin | ????100％????????n.d.?????＞100 | |
| ST1516 | Heparin | |
| 40%RO | ????100％????????n.d.?????＞85％ | |
| ST1514 | Heparin～50%RO | ????100％????????100％????＞85％ |
| ST1515 | Heparin 27.5%RO | ????100％????????100％????100 |
| ST1518 | ||
| 50 |
????100％????????100％????＞85％ |
Even it should be noted that under the concentration of 1 μ g/ml, ST1518 also has the high activity that suppresses.
The identical experiment model that use is described in WO 01/55221 is measured The compounds of this invention, the particularly noval chemical compound activity for the FGF somatomedin, and the result shows that they show and the suitable activity of disclosed chemical compound in citing document.
The following example is further for example understood the present invention.
Embodiment 1
ST1518
Excess pyridine is added in the aqueous solution of 1g heparin, wherein said heparin elutes from Amberlite IR 120 posts in advance.With this solution decompression evaporation; The heparin pyridiniujm of gained is dissolved in 50ml DMSO/H
2In 95: 5 mixture of O, stir 2 hours to obtain about 50% desulfurization acescency at 20 ℃.
Dilute this solution with isopyknic saturated sodium bicarbonate solution then.The distilled water that is used in the film (is 1000-2000D by molecular weight) is dialysed this solution.Isolate end-product by reduction vaporization.
By 50%N-desulfurization acidify heparin N-acetylation is prepared N-acetylation heparin.The 1g heparin is dissolved in the 10ml distilled water; This solution is cooled to 4 ℃, saturated with sodium bicarbonate; In this solution, add 625 μ l acetic anhydrides, this mixture was stirred 2 hours at 4 ℃.During reaction, control pH and be maintained at about 8 by adding sodium bicarbonate.The distilled water that is used in then in the film (is 2000-1000D by molecular weight) is dialysed gained solution.
This 50%N-acetylation heparin of 1g is dissolved in the 25ml distilled water, and is cooled to 4 ℃.Add 25ml NaIO
40.2M behind the solution, this solution was stirred 20 hours under dark condition, stop this reaction by adding ethylene glycol, and remove by tangential ultrafiltration and to desalt.In the solution of this desalination, add 400mg NaBH in batches
4With this solution stirring at room 3 hours, then with the dilute hydrochloric acid neutralization, by the tangential ultrafiltration desalination.
This chemical compound
13C NMR spectrum as shown in Figure 1.
ST2010 and ST2184
The 5g heparin is dissolved in the 63ml NaOH 1N solution.This solution was stirred 45 minutes at 60 ℃, cool off, and neutralize with dilute hydrochloric acid.Then this solution was stirred 48 hours at 70 ℃, cooling is used in the water dialysis in the film (is 2000-1000D by molecular weight).
2g2-O-desulfurization acidify heparin is dissolved in the 50ml distilled water, is cooled to 4 ℃.Add 50ml NaIO
40.2M behind the solution, this solution was stirred 20 hours under dark condition, stop this reaction by adding ethylene glycol, remove by tangential ultrafiltration and desalt.In the solution of this desalination, add 800mg NaBH in batches
4With this solution stirring at room 3 hours, then with the dilute hydrochloric acid neutralization, by the tangential ultrafiltration desalination.
The OR heparin of 400mg is dissolved in the 25ml distilled water.Add 7mgNaNO
2After,, with pH regulator to 2 this solution was stirred 17 minutes at 4 ℃ with dilute hydrochloric acid.Stop this reaction by neutralization.In the solution of this desalination, add 60mg NaBH in batches
4This solution stirring at room 3 hours, with the dilute hydrochloric acid neutralization, is come fractionated by gel filtration then.Isolate two level part: ST2010, have Mw=3050 with different molecular weight; And ST2184, have Mn=5800, Mw=7520.
Compound S T2010's
13C NMR spectrum as shown in Figure 2.
ST2041
Excess pyridine is added in the aqueous solution of 2g heparin, wherein said heparin elutes from Amberlite IR 120 posts in advance.With this solution decompression evaporation; The heparin pyridiniujm of gained is dissolved in 100ml DMSO/H
2In 95: 5 mixture of O, stirred 4 hours, to obtain about 64% desulfurization acescency at 20 ℃.
Dilute this solution with isopyknic saturated sodium bicarbonate solution then.The distilled water that is used in the film (is 1000-2000D by molecular weight) is dialysed this solution.Isolate end-product by reduction vaporization.
Compound S T2041's
13C NMR spectrum as shown in Figure 3.
Claims (24)
1. glycosaminoglycans derivant, the particularly desulfurization acescency desulfurization acidify heparin that is no more than total alduronic acid unitary 60% has heparinoid enzyme inhibition activity and/or FGF somatomedin in preparation and suppresses application in the active medicine.
2. the application of claim 1, wherein said derivant are heparin sample glycosaminoglycans.
3. claim 1 or 2 application, wherein said derivant are to comprise to have different N-desulfurization acescency and the optional modification heparin of the glycosamine residue of N-acidylate wholly or in part subsequently.
4. claim 1 or 3 application, wherein said derivant has following formula (I):
Wherein the U ring can have following meanings:
X and X ' can be identical or different, be aldehyde radical or-CH
2-D group, wherein D is the residue of hydroxyl or aminoacid, peptide or sugar or oligosaccharide;
R and R
1Can be identical or different, be SO
3, C
1-C
8Acyl residue, described residue can be chosen wantonly and carry at least one other carboxyl;
N and m can be identical or different, can be 1-40; N+m's and be 6-40; M: the n ratio is 10: 2-1: 1;
Symbol
Be meant that the unit of representing with m and n is along the polysaccharide chain statistical distribution, and need not to distribute in order.
5. the application of the derivant of claim 4, wherein R or R
1Be the N-acyl group, and be R+R
1The 40-60% of sum.
6. claim 4 or 5 application, wherein R that can be identical or different and R
1It is acetyl group.
7. each the application of derivant of claim 4-6, wherein m is more than or equal to n.
8. the application of claim 5 or 6 derivant, wherein n is the 40-60% of m+n sum.
9. the application of claim 4, wherein said derivant is selected from
The acidifying heparin of-part 2-O-desulfurization, its molecular weight (MW) is 11200, and polydispersity index D is 1.3, and the desulfurization acescency is 1.99 (with SO
3 -: COO
-Mol ratio is represented), the percentage ratio that the alduronic acid of modification accounts for total alduronic acid is about 50%, m: n=1: 1, and be to distribute along polysaccharide chain with rule, alternative mode with the unit that m and n represent;
The acidifying LMW heparin of-part 2-O-desulfurization, its molecular weight (MW) is 3050, and polydispersity index is 2.2, and the desulfurization acescency is 1.99 (with SO
3 -: COO
-Mol ratio is represented), the percentage ratio that the alduronic acid of modification accounts for total alduronic acid is about 50%.M: n=1: 1, and with the unit that m and n represent be with rule, alternative mode distributes along polysaccharide chain;
The acidifying LMW heparin of-part 2-O-desulfurization, its molecular weight is Mn=5800, Mw=7520, polydispersity index is 1.294, the percentage ratio that the alduronic acid of modifying accounts for total alduronic acid is about 50%, m: n=1: 1, and be to distribute along polysaccharide chain with rule, alternative mode with the unit that m and n represent;
-part 2-O-desulfurization acidify heparin, its molecular weight (MW) is 12900D, and polydispersity index D is 1.5, and the desulfurization acescency is 1.9 (with SO
3 -: COO
-Mol ratio is represented), the percentage ratio that the alduronic acid of modification accounts for total alduronic acid is: 5% epoxy radicals, 29% oxidation and reductive uronic acid residue, m: n=1: 1, and with the unit that m and n represent be with rule, alternative mode distributes along polysaccharide chain;
-part 2-O-desulfurization acidify heparin, its molecular weight (MW) is 9200D, polydispersity index D is 1.5, the percentage ratio that the alduronic acid of modifying accounts for total alduronic acid is: 11% epoxy radicals, 27.5% oxidation and reductive uronic acid residue, m: n=1: 1, and with the unit that m and n represent be with rule, alternative mode distributes along polysaccharide chain;
-2-O-desulfurization acidify heparin, its molecular weight (MW) is 11000D, and polydispersity index D is 1.5, and the desulfurization acescency is 1.93 (with SO
3 -: COO
-Mol ratio is represented), the percentage ratio that the alduronic acid of modification accounts for total alduronic acid is: 5% epoxy radicals, 29% oxidation and reductive uronic acid residue.
10. the application of claim 4, wherein said derivant is selected from
-part N-desulfurization acidify and N-reacetylation heparin, its molecular weight (MW) is 11250, and polydispersity index is 1.66, and the desulfurization acescency is 1.7 (with SO
3 -: COO
-Mol ratio is represented), the percentage ratio that the alduronic acid of modification accounts for total alduronic acid is about 30%, R+R
150% of sum is the N-acetyl group;
-part N-desulfurization acidify and N-reacetylation LMW heparin, its molecular weight is Mn=4780, and Mw=10000, polydispersity index D are 2.092, and the percentage ratio that the alduronic acid of modification accounts for total alduronic acid is about 30%, R+R
150% of sum is the N-acetyl group;
-part N-desulfurization acidify and N-reacetylation heparin, its molecular weight is Mn=10890, Mw=22370, polydispersity index are 2.054, R+R
127% of sum is the N-acetyl group;
-part N-desulfurization acidify and N-reacetylation heparin, its molecular weight is Mn=10210, Mw=21270, polydispersity index are 2.083, R+R
139% of sum is the N-acetyl group;
-part N-desulfurization acidify and N-reacetylation heparin, its molecular weight is Mn=11070, Mw=22000, polydispersity index are 1.987, R+R
164% of sum is the N-acetyl group;
-part N-desulfurization acidify and N-reacetylation heparin, wherein to account for the percentage ratio of total alduronic acid be about 30% to the alduronic acid of Xiu Shiing, R+R
127% of sum is the N-acetyl group;
-part N-desulfurization acidify and N-reacetylation heparin, wherein to account for the percentage ratio of total alduronic acid be about 30% to the alduronic acid of Xiu Shiing, R+R
139% of sum is the N-acetyl group;
-part N-desulfurization acidify and N-reacetylation heparin, wherein to account for the percentage ratio of total alduronic acid be about 30% to the alduronic acid of Xiu Shiing, R+R
164% of sum is the N-acetyl group.
11. each application of claim 1-10, wherein said medicine has anti-angiogenesis activity.
12. each application of claim 1-10, wherein said medicine can be used for treating inflammation.
13. each application of claim 1-10, wherein said medicine can be used for treating autoimmune disease.
14. each application of claim 1-10, the disease of wherein said desire treatment is selected from primary tumor, metastatic tumor, diabetic retinopathy, psoriasis, retrolental fibroplasia, the restenosis of postangioplasty, coronary artery bypass, inflammation, arthritis, autoimmune disease, homograft rejection, cardiovascular disease, the fiber proliferative disease, the disease that unusual platelet aggregation causes, the disease that smooth muscle proliferation causes, the Goodpasture syndrome, acute glomerulonephritis, the neonate pulmonary hypertension, asthma, congestive heart failure, adult's pulmonary hypertension, renal vascular hypertension, proliferating retinopathy, multiple sclerosis, experimental autoimmune encephalomyelitis, insulin dependent diabetes mellitus (IDDM), inflammatory bowel, ulcerative colitis, segmental enteritis.
15. formula (I) chemical compound:
Wherein the U ring can have following meanings:
X and X ' can be identical or different, be aldehyde radical or-CH
2-D group, wherein D is the residue of hydroxyl or aminoacid, peptide or sugar or oligosaccharide;
R and R
1Can be identical or different, be SO
3, C
1Or C
3-C
8Acyl residue;
N and m can be identical or different, can be 1-40; N+m's and be 6-40; M: the n ratio is 10: 2-1: 1; Symbol
Be meant that the unit of representing with m and n is along the polysaccharide chain statistical distribution, and need not to distribute in order.
16. the chemical compound of claim 15, wherein said chemical compound is selected from:
-part N-desulfurization acidify and N-reacetylation heparin, its molecular weight (MW) is 11250, and polydispersity index is 1.66, and the desulfurization acescency is 1.7 (with SO
3 -: COO
-Mol ratio is represented), the percentage ratio that the alduronic acid of modification accounts for total alduronic acid is about 30%, R+R
150% of sum is the N-acetyl group;
-part N-desulfurization acidify and N-reacetylation LMW heparin, its molecular weight is Mn=4780, and Mw=10000, polydispersity index are 2.092, and the percentage ratio that the alduronic acid of modification accounts for total alduronic acid is about 30%, R+R
150% of sum is the N-acetyl group;
-part N-desulfurization acidify and N-reacetylation heparin, its molecular weight is Mn=10890, Mw=22370, polydispersity index are 2.054, R+R
127% of sum is the N-acetyl group;
-part N-desulfurization acidify and N-reacetylation heparin, its molecular weight is Mn=10210, Mw=21270, polydispersity index are 2.083, R+R
139% of sum is the N-acetyl group;
-part N-desulfurization acidify and N-reacetylation heparin, its molecular weight is Mn=11070, Mw=22000, polydispersity index are 1.987, R+R
164% of sum is the N-acetyl group;
-part N-desulfurization acidify and N-reacetylation heparin, wherein to account for the percentage ratio of total alduronic acid be about 30% to the alduronic acid of Xiu Shiing, R+R
127% of sum is the N-acetyl group.
17. the method for the chemical compound of preparation claim 15 or 16, described method comprises the following steps:
A) carry out N-desulfurization acidify by following operation: with the sulfoamino-group residue at DMSO: H
2O95: 5 V: solvolysis hydrolysis 0.5-8 hour under room temperature among the V, to remove sulfate groups wholly or in part in glycosamine residue 2-position;
B) by following operation with described in glycosamine residue 2-position the acidifying group N-of desulfurization acidylate wholly or in part: in alkaline aqueous solution (pH 8-9), handle, to be created on the glycosamine residue 2-position group of acidylate wholly or in part with acylating agent; Then the gained chemical compound is carried out following step c), d) or e) and f-g) handle, or directly carry out following step f) and handle;
C) carry out alkali treatment in room temperature to about 100 ℃ of temperature, cause being removed and forming epoxide group in the sulfate groups of the control percentage ratio of iduronic acid 2-position; If necessary
D), under about 50 ℃-Yue 100 ℃ of temperature, open described epoxide ring, to produce the galacturonic acid residue at about pH 7; Perhaps
E) under about 0 ℃ of-30 ℃ of temperature, open described epoxide ring, to produce the iduronic acid residue; If necessary
F) with sodium metaperiodate with glycol oxidation, to open the glucosides ring and to form the residue of 2 aldehyde radical/modifications;
G) described aldehyde radical is reduced into primary alconol and if necessary, the represented non-hydroxyl group of different implications that the D groups converted is become as provides in formula (I);
H) optional the chemical compound that obtains is carried out acid hydrolysis in step g), to obtain and the corresponding oligosaccharide of sequence of rules; Perhaps
I) with the enzyme or the coordinate that are selected from lyases, heparinase, heparanase the product that obtains is carried out the part enzymatic hydrolysis in step g), to obtain oligosaccharide, preferred tetrose or eight sugar, it has the non-reduced terminal residue of being made up of unsaturated iduronic acid, the reduction residue of forming by the N-glucosamine sulfate, and contain the iduronic acid residue of at least one open loop;
J) optionally handle chemical compound that in step c), obtains or the product that in step d), obtains by the part enzymatic hydrolysis; If necessary
K) will be at step b), c) and one of f) in the product part 6-O-desulfurization acidify that obtains; Perhaps
L) partially or completely the acidifying initial heparin of 6-desulfurization carries out step b), c) and f).
18. the chemical compound that can obtain by the method for claim 17.
19. the chemical compound that can obtain by the method for claim 17, wherein said chemical compound is selected from:
-heparin N-acetyl group (50%); wherein step a) was carried out 2 hours in room temperature; step b) was carried out 2 hours at 4 ℃; step c), d), e) save; step f) is carried out a night at 4 ℃, and step g) was carried out 3 hours in room temperature, and its molecular weight (MW) is 11200; polydispersity index D is 1.3, and the desulfurization acescency is 1.6 (with SO
3 -: COO
-Mol ratio is represented), the percentage ratio that the alduronic acid of modification accounts for total alduronic acid is about 50%;
-LMW heparin N-acetyl group (50%), wherein step a) was carried out 2 hours in room temperature, and step b) was carried out step c), d 2 hours at 4 ℃), e) save, step f) is carried out a night at 4 ℃, step g) was carried out 3 hours in room temperature, step h) by carrying out 17 minutes based on 4 ℃, aldehyde radical was reduced 3 hours in room temperature with boron hydride then with the nitrous acid deamination, its molecular weight is Mw=4780, Mn=10000, polydispersity index D are 2.092, and the percentage ratio that the alduronic acid of modification accounts for total alduronic acid is about 30%;
-heparin N-acetyl group (27%), wherein step a) was carried out 2 hours in room temperature, step b) was carried out step c), d 2 hours at 4 ℃), e), f), g), h) save, its molecular weight is Mn=10890, Mw=22370, polydispersity index D are 2.054;
-heparin N-acetyl group (39%), wherein step a) was carried out 2 hours in room temperature, step b) was carried out step c), d 2 hours at 4 ℃), e), f), g), h) save, its molecular weight is Mn=10210, Mw=21270, polydispersity index D are 2.083;
-heparin N-acetyl group (64%), wherein step a) was carried out 2 hours in room temperature, step b) was carried out step c), d 2 hours at 4 ℃), e), f), g), h) save, its molecular weight is Mn=11070, Mw=22000, polydispersity index D are 1.987;
-heparin N-acetyl group (27%), wherein step a) was carried out 2 hours in room temperature, step b) was carried out step c), d 2 hours at 4 ℃), e), f), g), h) save, the percentage ratio that the alduronic acid of modification accounts for total alduronic acid is about 30%;
-heparin N-acetyl group (39%), wherein step a) was carried out 2 hours in room temperature, step b) was carried out step c), d 2 hours at 4 ℃), e), f), g), h) save, the percentage ratio that the alduronic acid of modification accounts for total alduronic acid is about 30%;
-heparin N-acetyl group (64%) can obtain by said method, and wherein step a) was carried out 2 hours in room temperature, and step b) was carried out step c), d 2 hours at 4 ℃), e), f), g), h) save, the percentage ratio that the alduronic acid of modification accounts for total alduronic acid is about 30%.
20. pharmaceutical composition, the chemical compound that wherein comprises at least a claim 15 or 16 and/or 19 is as active component and pharmaceutically suitable carrier blended with it and excipient.
21. the chemical compound of claim 15-16 and 19 is as the application of medicine.
22. the chemical compound of claim 15-16 and 19 is as the application of pharmaceutical carrier.
23. the application of claim 22, wherein said medicine are selected from steroidal and nonsteroidal anti-inflammatory drug, corticosteroid, have the medicine of metastasis effect, the medicine that acts on endothelin level.
24. the application of claim 23, wherein said anti-metastasis drug is an inhibitors of metalloproteinase.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IT2001/000472 WO2003022291A1 (en) | 2001-09-12 | 2001-09-12 | Derivatives of partially desulphated glycosaminoglycans as heparanase inhibitors, endowed with antiangiogenic activity and devoid of anticoagulating effect |
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|---|---|
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| CN1547477B CN1547477B (en) | 2010-12-22 |
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|---|---|
| US (1) | US20050137167A1 (en) |
| EP (2) | EP2343077B1 (en) |
| JP (1) | JP2005506326A (en) |
| KR (1) | KR100855331B1 (en) |
| CN (1) | CN1547477B (en) |
| AT (1) | ATE511846T1 (en) |
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| CZ (1) | CZ307433B6 (en) |
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| CN105814086A (en) * | 2013-10-31 | 2016-07-27 | ＂G.龙佐尼＂ S.R.生化高科技研究中心 | Derivatives of n-desulfated glucosaminoglycans and use as drugs |
| WO2018149320A1 (en) * | 2017-02-15 | 2018-08-23 | 清华大学 | Non-anticoagulant heparin derivative and use thereof in treating inflammatory bowel disease |
| CN105744940B (en) * | 2013-11-06 | 2019-06-25 | 诺瓦健康生物系统有限公司 | The carboxylated derivative of glycosaminoglycan and purposes as drug |
| WO2019149179A1 (en) * | 2018-02-02 | 2019-08-08 | 深圳市海普瑞药业集团股份有限公司 | Glycosaminoglycan derivative and preparation method therefor and use thereof |
| WO2021128253A1 (en) * | 2019-12-27 | 2021-07-01 | 深圳市海普瑞药业集团股份有限公司 | Glycosaminoglycan derivative and application thereof |
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| US11370848B2 (en) | 2013-11-06 | 2022-06-28 | Novahealth Biosystems, Llc | Carboxylated derivatives of glycosaminoglycans and use as drugs |
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| US11332548B2 (en) | 2013-11-06 | 2022-05-17 | Novahealth Biosystems, Llc | Carboxylated derivatives of glycosaminoglycans and use as drugs |
| CN110218268B (en) * | 2013-11-06 | 2021-10-15 | 诺瓦健康生物系统有限公司 | Carboxylated derivatives of glycosaminoglycans and use as medicaments |
| WO2018149320A1 (en) * | 2017-02-15 | 2018-08-23 | 清华大学 | Non-anticoagulant heparin derivative and use thereof in treating inflammatory bowel disease |
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| CN114901702A (en) * | 2019-12-27 | 2022-08-12 | 深圳市海普瑞药业集团股份有限公司 | Glycosaminoglycan derivative and application thereof |
| CN114901702B (en) * | 2019-12-27 | 2024-01-09 | 深圳市海普瑞药业集团股份有限公司 | Glycosaminoglycan derivative and application thereof |
Also Published As
| Publication number | Publication date |
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| PT1427427E (en) | 2011-09-13 |
| HU230385B1 (en) | 2016-03-29 |
| ES2367778T3 (en) | 2011-11-08 |
| WO2003022291A1 (en) | 2003-03-20 |
| EP2343077B1 (en) | 2013-07-17 |
| PT2343077E (en) | 2013-08-29 |
| CZ2004255A3 (en) | 2004-11-10 |
| EP1427427B1 (en) | 2011-06-08 |
| HUP0401693A3 (en) | 2009-06-29 |
| CA2457719A1 (en) | 2003-03-20 |
| ES2431362T3 (en) | 2013-11-26 |
| BR0117124A (en) | 2004-09-28 |
| HK1069537A1 (en) | 2005-05-27 |
| MXPA04002217A (en) | 2004-07-08 |
| KR20040048404A (en) | 2004-06-09 |
| JP2005506326A (en) | 2005-03-03 |
| CA2457719C (en) | 2012-01-03 |
| EP1427427A1 (en) | 2004-06-16 |
| CY1114544T1 (en) | 2016-10-05 |
| US20050137167A1 (en) | 2005-06-23 |
| KR100855331B1 (en) | 2008-09-04 |
| DK1427427T3 (en) | 2011-09-19 |
| EP2343077A1 (en) | 2011-07-13 |
| CN1547477B (en) | 2010-12-22 |
| CY1112551T1 (en) | 2016-02-10 |
| CZ307433B6 (en) | 2018-08-22 |
| ATE511846T1 (en) | 2011-06-15 |
| SI1427427T1 (en) | 2011-10-28 |
| SK288335B6 (en) | 2016-02-02 |
| HUP0401693A2 (en) | 2004-12-28 |
| SK1602004A3 (en) | 2004-08-03 |
| AU2001292231B2 (en) | 2008-06-05 |
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